The introduction of aggressive multi-modality treatments have helped cancer survivors live longer than before. Many cancer treatments have deleterious side-effects, which also manifest in the oral cavity. Oral complications predominantly affect patients undergoing radiotherapy for head and neck cancers, early stage lymphomas, and full-body radiation before bone marrow transplantation. The most common and distressing oral symptom of radiotherapy is reduced saliva. The unintended destruction of normal salivary glands causes a dramatic drop in saliva production, leading to a condition referred to as xerostomia or dry mouth. Reduced saliva in the mouth causes intense burning pain and makes basic functions such as tasting, chewing, swallowing, and speaking difficult to perform. It also contributes to the risk of oral infections, ulcerations, and rapid tooth decay. The morbidity associated with xerostomia severely compromises a patient's quality of life, their nutritional intake and their ability to continue cancer treatment. There is no cure for xerostomia, and emphasis is now increasingly placed on prevention. Introduction of new radiotherapy techniques to spare the salivary glands has helped reduce, to some measure, the severity of the condition, but not its prevalence. The treatment of xerostomia continues to be a challenge. We had previously found that increased levels of a normal cellular protein, Tousled-like kinase 1B (TLK1B), can protect normal epithelial cells against radiation-induced cell death. Recently, we demonstrated that this cytoprotective effect is reproducible in rat salivary cells, and cell-permeable TLK1B can attenuate radiation-induced salivary hypofunction in rats. To determine the most viable approach for clinical translation, in the proposed study we will examine 1) whether improved penetration of TLK1B using analogs of HIV-TAT protein transduction domain can increase survival of human salivary acinar cells against radiation, and 2) whether activation of endogenous TLK1B using small molecules can protect against radiation-induced cell death. The results of our studies will further the preclinical development of TLK1B protein therapy and assess the applicability of its activators in ameliorating radiation- induced xerostomia. Future research can then be directed at determining whether a combination of protein and drug therapy will be more efficacious than either treatment alone. Prevention of xerostomia will not only improve a patient's treatment compliance and therefore, cancer prognosis, but also his quality of life and self-esteem as a cancer survivor. PUBLIC HEALTH RELEVANCE: Great strides in understanding the molecular mechanisms of carcinogenesis have helped the fight against cancer. The introduction of aggressive, multi-modality treatments has seen many cancer survivors live longer than before, but the accompanying deleterious side-effects of these treatments diminish the patient's quality of life. In this proposal we seek to further develop a preventive protein therapy and evaluate the efficacy of drugs that activate it in ameliorating the adverse effect of radiotherapy, salivary hypofunction.